DE2336401C3 - Tri-p-toluenesulfonate of S-adenosyl-L-methionine, processes for its preparation and therapeutic agents containing it - Google Patents
Tri-p-toluenesulfonate of S-adenosyl-L-methionine, processes for its preparation and therapeutic agents containing itInfo
- Publication number
- DE2336401C3 DE2336401C3 DE2336401A DE2336401A DE2336401C3 DE 2336401 C3 DE2336401 C3 DE 2336401C3 DE 2336401 A DE2336401 A DE 2336401A DE 2336401 A DE2336401 A DE 2336401A DE 2336401 C3 DE2336401 C3 DE 2336401C3
- Authority
- DE
- Germany
- Prior art keywords
- sam
- solution
- tri
- toluenesulfonate
- toluenesulfonic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 title claims description 58
- 238000000034 method Methods 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 4
- 239000003814 drug Substances 0.000 title description 2
- 229940124597 therapeutic agent Drugs 0.000 title 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 23
- 150000003839 salts Chemical class 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- 230000004060 metabolic process Effects 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 8
- 150000001768 cations Chemical class 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 7
- 150000001450 anions Chemical group 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000007069 methylation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- -1 Aminopropyl group Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000235646 Cyberlindnera jadinii Species 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000002934 lysing effect Effects 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229960004452 methionine Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical group S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000007357 Methionine adenosyltransferase Human genes 0.000 description 1
- 108010007784 Methionine adenosyltransferase Proteins 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DYFPQIYEZQULMZ-XKGORWRGSA-N [(3s)-3-amino-3-carboxypropyl]-[[(2s,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl]-methylsulfanium;chloride Chemical compound [Cl-].O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 DYFPQIYEZQULMZ-XKGORWRGSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 208000020442 loss of weight Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 229940082632 vitamin b12 and folic acid Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/38—Nucleosides
- C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
Description
CH-CH-CH-CH-CH2-S-CH2-Ch2-CH-COOH · 2CH3-QH4-SO-4H OH OH CH3-CH4SO.,CH-CH-CH-CH-CH 2 -S-CH 2 -Ch 2 -CH-COOH · 2CH 3 -QH 4 -SO -4 H OH OH CH 3 -CH 4 SO.,
2. Verfahren zur Herstellung von Tri-p-toluolsulfonat von S-Adenosyl-L-methionin gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine wäßrige Lösung, die SAM und p-Toluolsulfonsäure in einem Molverhältnis von 1 zu 3 bis 10 enthält, herstellt, die wäßrige Lösung, falls erforderlich, 2; konzentriert und das Salz durch Zugeben eines organischen, in Wasser löslichen Lösungsmittels ausfällt.2. Process for the preparation of tri-p-toluenesulfonate of S-adenosyl-L-methionine according to claim 1, characterized in that one aqueous solution, the SAM and p-toluenesulfonic acid contains in a molar ratio of 1 to 3 to 10, prepares the aqueous solution, if necessary, 2; concentrated and the salt by adding an organic, water-soluble solvent fails.
3. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, daß das Molverhältnis von SAM zu jo p-Toluolsulfonsäure 1 zu 6 beträgt.3. The method according to claim 2, characterized in that the molar ratio of SAM to jo p-Toluenesulfonic acid is 1 to 6.
NH2 NH 2
4. Arzneimittel, enthaltend die Verbindung des Anspruchs 1 in einem üblichen, pharmazeutisch verträglichen Träger.4. Medicament containing the compound of claim 1 in a conventional, pharmaceutical compatible carrier.
S-Adenosyl-L-methionin (SAM) ist ein Produkt, das in allen lebenden Organismen, von Bakterien bis Pflanzen, von einzelligen Organismen bis zu höheren Säugetieren und beim Menschen vorkommt und das durch folgende Formel gekennzeichnet ist:S-Adenosyl-L-methionine (SAM) is a product that is used in all living organisms, from bacteria to plants, from unicellular organisms to higher mammals and occurs in humans and is characterized by the following formula:
N NN N
CH3 CH 3
NH2 NH 2
CH-CH-CH-CH-CH2-S-Ch2-CH2-CH-COOH OH OH X CH-CH-CH-CH-CH 2 -S-Ch 2 -CH 2 -CH-COOH OH OH X
O-O-
worin X ein Anion bedeutet.wherein X is an anion.
lii lebenden Organismen wird SAM durch Einwirken von Enzymen (S-Adenosylmethioninsynthetase oder S-Adenosyltransferase) im cytoplasmatischen Bereich aus Methionin, das mit den Nahrungsmitteln aufgenommen wird, und ATP, das als Energiereserve in jeder lebenden Zelle vorhanden ist, gebildet.lii living organisms becomes SAM by acting of enzymes (S-adenosylmethionine synthetase or S-adenosyltransferase) in the cytoplasmic area from methionine, which is ingested with food, and ATP, which is an energy reserve in everyone living cell is present.
SAM ist der einzige spezifische Methylgruppenspender in lebenden Organismen für die biochemische Reaktion der Übertragung der CH3-Gruppe, die eine fundamentale Reaktion im Fett-, Eiweiß- und Zuckerstoffwechsel ist. SAM-abhängige Methylierungsreaktionen umfassen: N-Methylierungen.O-Methylierungen, S-Methylierungen und C-Methylierungen.SAM is the only specific methyl group donor in living organisms for biochemical Reaction of the transfer of the CH3 group, which is a fundamental reaction in fat, protein and sugar metabolism is. SAM-dependent methylation reactions include: N-methylations, O-methylations, S-methylations and C-methylations.
Dies bedeutet unter Bezugnahme auf den menschlichen Organismus, daß SAM in den folgenden Stoffwechselvorgängen mitwirkt:With reference to the human organism, this means that SAM in the following Metabolic processes are involved:
Biosynthese von Cholin, Biosynthese von Phosphatidylcholin. Bildung von Enzymen, die SH-Gruppen benötigen, Catecholaminstoffwechsel, Stoffwechsel biogener zentralcephaler Amine, Serotoninstoffwechsel, Histaminstoffwechsel, Vitamin B 12- und Folsäurestoffwechsel, Keratinstoffwechsel, Myosinstoffwechsel, Stoffwechsel von Histonen, Stoffwechsel von RNA, Stoffwechsel von DNA, Stoffwechsel von Proteinsubstanzen, Stoffwechsel einiger Hormone mit Cyclopentanperhydrophenantrenkern, wovon die hauptsächlichsten die östrogene sind, Stoffwechsel der Triglyceride.Biosynthesis of choline, biosynthesis of phosphatidylcholine. Formation of enzymes that need SH groups, catecholamine metabolism, metabolism biogenic central cephalic amines, serotonin metabolism, histamine metabolism, vitamin B 12 and Folic acid metabolism, keratin metabolism, myosin metabolism, metabolism of histones, metabolism of RNA, metabolism of DNA, metabolism of protein substances, metabolism of some hormones with Cyclopentane perhydrophenantrenkern, of which the main ones are the estrogens, metabolism of Triglycerides.
Durch die Entmethylierung wird SAM in S-Adenosyl-The demethylation transforms SAM into S-adenosyl
T, homocystein (SAO) umgewandelt, das ein indirekter Spender von Hydrosulfidgruppen ist und somit eine entscheidende Bedeutung im Stoffwechsel aller Verbindungen hat, die zur Durchführung ihrer biologischen Aktivität SH-Gruppen benötigen. Darunter sind vonT, converted to homocysteine (SAO), which is an indirect It is a donor of hydrosulphide groups and is therefore of crucial importance in the metabolism of all compounds who need SH groups to carry out their biological activity. Among them are from
ho besonderer Bedeutung einige Bioenzyme und die sulfurierlen Aminosäuren.ho particular importance some bioenzymes and the sulphurized amino acids.
SAO wiederum wird im Organismus decarboxyliert und das decarboxylierte Produkt ist die Hauptquelle der Aminopropylgruppe, die — gemäß den neuestenSAO, in turn, is decarboxylated in the organism and the decarboxylated product is the main source of the Aminopropyl group, which - according to the latest
t,5 biochemischen Erkenntnissen — für die Biosynthese von Polyamin unerläßlich ist.t, 5 biochemical findings - for biosynthesis of polyamine is indispensable.
Auf Grund dieses Wissens kann angenommen werden, daß SAM bei der Behandlung pathologischerBased on this knowledge, it can be assumed that SAM may be used in the treatment of pathological
Zustände, die mit der Störung der oben erwähnten Stoffwechselvorgänge zusammenhängen, einige therapeutische Wirkung haben könnte.Conditions related to the disorder mentioned above Metabolic processes related, could have some therapeutic effects.
Die außerordentliche Instabilität der bisher bekannten Salze von SAM unter normalen Umgebungsbedingungen hat es verhindert, daß pharmakologische oder klinische Tests in größerem Umfang durchgeführt wurden und hat so auch eine breitere praktische Verwendung in der Humantherapie verhindertThe extraordinary instability of the previously known Salts of SAM under normal environmental conditions has prevented it from being pharmacological or clinical tests have been carried out on a larger scale and so has also a broader practical one Prevented use in human therapy
Es wurde nun völlig unerwartet ein neues Salz von SAM gefunden, das bei Umgebungstemperatur praktisch unbegrenzt stabil ist und das industriell mit hohen Ausbeuten und wirtschaftlich hergestellt werden kann.Now, completely unexpectedly, a new salt of SAM has been found that works at ambient temperature is indefinitely stable and which can be produced industrially with high yields and economically.
Das erfindungsgemäße neue Salz ist ein Salz von SAM mit p-Toluolsulfonsäure der FormelThe new salt according to the invention is a salt of SAM with p-toluenesulfonic acid of the formula
.SAM+CH3C6H4SO3" · 2 CH3C6H4SO3H,.SAM + CH 3 C 6 H 4 SO 3 "· 2 CH 3 C 6 H 4 SO 3 H,
das zum Zwecke der Beschreibung der vorliegenden Erfindung der Einfachheit halber SAM ■ C2IH23S3O9 genannt wird.which for the purpose of describing the present invention is called SAM ■ C 2 IH 23 S 3 O 9 for the sake of simplicity.
Die Höhe des technischen Fortschritts ist aus der nachstehenden Tabelle zu entnehmen, worin die zeitliche Stabilität bei 25° C in trockenem Zustand der beiden bisher bekannten stabilsten SAM-Salze, nämlich des Chlorids und des sauren Sulfats (SAM+HSO4-) und des neuen Tri-p-toluolsulfonats verglichen werden. Die Zahlen geben den Prozentsatz an verbleibendem SAM nach den angegebenen Zeitspannen an:The level of technical progress is shown in the table below, which shows the stability over time at 25 ° C in the dry state of the two most stable SAM salts known to date, namely the chloride and the acid sulphate (SAM + HSO 4 -) and the new one Tri-p-toluenesulfonate can be compared. The numbers indicate the percentage of SAM remaining after the specified time periods:
3030th
30 Tage 180 Tage 360 Tage 540 Tage30 days 180 days 360 days 540 days
84,284.2
80,180.1
Das erfindungsgemäße Salz wird dadurch gewonnen, daß man eine wäßrige Lösung, die SAM und p-Toluolsulfonsäure im Verhältnis 1 Mol zu 3 bis 10 Mol enthält, herstellt, die wäßrige Lösung, falls erforderlich, konzentriert und das Salz durch Zugeben eines organischen, in Wasser löslichen Lösungsmittels ausfällt. Zur Fällung eignen sich beispielsweise Äthyl-, Propyl-, Isopropylalkohol, Aceton, Methylethylketon.The salt according to the invention is obtained by an aqueous solution, the SAM and contains p-toluenesulfonic acid in a ratio of 1 mole to 3 to 10 moles, the aqueous solution, if necessary, concentrated and the salt precipitated by adding an organic, water-soluble solvent. For example, ethyl, propyl, isopropyl alcohol, acetone and methyl ethyl ketone are suitable for precipitation.
Falls bei der Herstellung des erfindungsgemäßen Salzes von Hefe (Saccharomyces Cerevisiae, Torulopsis utilis, Candida utilis), angereichert an SAM durch Zugabe von Methionin unter geeigneten Wachstums- w bedingungen (vgl. S c h I e η k, Enzymologia 29, 283 [1965]), ausgegangen wird, umfaßt das Verfahren zur Herstellung des neuen Salzes vorzugsweise im wesentlichen die folgenden Stufen: .In the preparation of the salt according to the invention by yeast (Saccharomyces Cerevisiae, Torulopsis utilis, Candida utilis), enriched in SAM necessary by the addition of methionine under suitable growth conditions cf. w (. S ch I e η k, Enzymologia 29, 283 [1965] ), the process for the preparation of the new salt preferably comprises essentially the following steps:.
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(a) Behandeln der Hefe mit Äthyl- oder Methylacetat bei Umgebungstemperatur, um die Lysis der Zellen zu verursachen und das anwesende SAM in Lösung zu überführen;(a) Treating the yeast with ethyl or methyl acetate at ambient temperature to lyse the cells to cause and to convert the present SAM into solution;
(b) Adsorption der filtrierten wäßrigen Lösung in einer e>o Kolonne eines schwach sauren Kationenaustauschers in saurer Form;(b) Adsorption of the filtered aqueous solution in an e> o Column of a weakly acidic cation exchanger in acidic form;
(c) Entfernung der Verunreinigungen durch Waschen mit Wasser und dann mit 0,025 η Essigsäure;(c) removing the impurities by washing with water and then with 0.025 η acetic acid;
(d) Eluieren von SAM mit einer wäßrigen Lösung von t>-, p-Toluolsulfonsäure;(d) eluting SAM with an aqueous solution of t> -, p-toluenesulfonic acid;
(e) Neutralisation der überschüssigen p-Toluolsulfonsäure durch Behandeln mit einem stark oder schwach-basischen Anionenaustauscher (OH ~- Form), bis sich ein Mol verhältnis SAM zu p-Toluolsulfonsäure von 1 bis 3 bis 10, bevorzugt etwa 6, ergibt(e) Neutralization of the excess p-toluenesulfonic acid by treating with a strong or weakly basic anion exchanger (OH ~ - form), until a molar ratio of SAM to p-Toluenesulfonic acid from 1 to 3 to 10, preferably about 6, gives
Die Stufe (a) wird unter Verwendung einer Menge Acetat zwischen '/20 und Vs, bevorzugt 1Ao des Gewicht der feuchten Zellen während einer Zeitdauer von zwischen 30 Minuten und 2 Stunden, bevorzugt 1 Stunde, durchgeführtStep (a) is carried out using an amount of acetate between 1/20 and Vs, preferably 1 Ao, of the weight of the wet cells for a period of between 30 minutes and 2 hours, preferably 1 hour
In Stufe (d) können Lösungen bis zu 1-molarer Konzentration von p-Toluolsulfonsäure in Wasser verwendet werden.In stage (d), solutions of up to 1 molar concentration of p-toluenesulfonic acid in water can be used be used.
Es wurde gefunden, daß das angegebene Molverhältnis SAM: p-Toluolsulfonsäure kritisch ist hinsichtlich der Schaffung der besten Bedingungen zur quantitativen Ausfällung des erfindungsgemäßen Salzes aus der Lösung, in der alle anorganischen Kationsalze zusammen mit kleinen Mengen Verunreinigungen, die anwesend sein können, zurückbleiben.It has been found that the stated molar ratio SAM: p-toluenesulfonic acid is critical with regard to the creation of the best conditions for the quantitative precipitation of the salt according to the invention from the Solution in which all inorganic cation salts together with small amounts of impurities that can be present, lag behind.
Eine Modifikation des angegebenen Verfahrens besteht darin, daß man das auf dem schwach-sauren Kationenaustauscher adsorbierte SAM mit einer wäßrigen Lösung von Chlorwasserstoffsäure oder Schwefelsäure eluiert und nicht direkt mit p-Toluolsulfonsäure.A modification of the procedure given is that it is done on the weakly acidic Cation exchanger adsorbed SAM with an aqueous solution of hydrochloric acid or sulfuric acid eluted and not directly with p-toluenesulfonic acid.
Die Chlorid- und Sulfatanionen können aus dem Eluat, beispielsweise mit einem Anionenaustauscher, geeignet entfernt werden. Alternativ kann das Chlorid oder Sulfat von verunreinigtem SAM aus den Eluaten ausgefällt werden, nachdem man den Überschuß an Säure teilweise durch Eindampfen oder Behandeln mit einer geeigneten Base entfernt hat Das so ausgefällte Sulfat oder Chlorid wird in Wasser erneut gelöst, und nach Eliminieren des Anions und Zugabe von p-Toluolsulfonsäure in dem vorstehend beschriebenen Verhältnis wird das SAM-tri-p-toluolsulfonat ausgefällt.The chloride and sulfate anions can be extracted from the eluate, for example with an anion exchanger, be removed appropriately. Alternatively, the chloride or sulfate can be contaminated from SAM from the eluates be precipitated after the excess of acid partially by evaporation or treatment with a suitable base has removed the so precipitated sulfate or chloride is redissolved in water, and after eliminating the anion and adding p-toluenesulfonic acid in the one described above Ratio, the SAM-tri-p-toluenesulfonate is precipitated.
Andere starke Säuren können auf ähnliche Weise zur Eluierung von SAM verwendet werden, ohne daß sich jedoch besondere Vorteile ergeben.Other strong acids can be used in a similar manner to elute SAM without themselves however, result in particular advantages.
Das erfindungsgemäße Salz kann auch aus einer Lösung, die sich aus der enzymatischen Synthese oder chemischen Synthese von SAM ergibt, oder aus einer wäßrigen Lösung eines seiner löslichen Salze nach Zugabe von p-Toluolsulfonsäure im angegebenen Molverhältnis ausgefällt werden.The salt according to the invention can also be obtained from a solution resulting from enzymatic synthesis or chemical synthesis of SAM results, or one of its soluble salts from an aqueous solution Addition of p-toluenesulfonic acid in the specified molar ratio are precipitated.
Die nachfolgenden Beispiele veranschaulichen das erfindungsgemäße Verfahren zur Herstellung des neuen Salzes.The following examples illustrate the process according to the invention for preparing the new one Salt.
Zu 90 kg Hefe, die gemäß S c h I e η k (Enzymologia 29, 283 [1965]) mit 5,5 g/kg SAM angereichert ist, gibt man bei Umgebungstemperatur 9 1 Äthylacetat.To 90 kg of yeast which is enriched with 5.5 g / kg of SAM according to S c h I e η k (Enzymologia 29, 283 [1965]) one at ambient temperature 9 liters of ethyl acetate.
Nachdem man 1 Stunde kräftig gerührt hat, verdünnt man die Masse mit 40 kg Wasser. Man filtriert und wäscht und erhält 140 Liter Lösung, die 3,55 g/l SAM enthält, was 99,5% des im Ausgangsmaterial anwesenden entspricht. 14 Liter dieser Lösung adsorbiert man auf 1 Liter eines schwach-sauren Kationenaustauschers in der H+-Form und eluiert dann nacheinander a) mit Wasser, b) mit 0,025 η Essigsäure, c) mit einer 1-molaren Lösung von p-Toluolsulfonsäure. Die Fraktionen, die reich an praktisch reinem SAM sind Hestimmung durch Dünnschichtchromatographie gemäß Anal. Biochim. 4,16-28[197I]) ergaben insgesamt 1,8 Liter und enthielten 85% des in die Kolonne eingespeisten Produkts. Diese Lösung behandelte man mit 1,7 Liter eines Anionenaustauschers in derAfter stirring vigorously for 1 hour, the mass is diluted with 40 kg of water. One filtered and washes and receives 140 liters of solution containing 3.55 g / l SAM, which is 99.5% of that present in the starting material is equivalent to. 14 liters of this solution are adsorbed onto 1 liter of a weakly acidic cation exchanger in the H + form and then eluted successively a) with water, b) with 0.025 η acetic acid, c) with a 1 molar solution of p-toluenesulfonic acid. The fractions that are rich in practically pure SAM Determination by thin layer chromatography according to Anal. Biochim. 4,16-28 [197I]) gave a total of 1.8 liters and contained 85% of the product fed into the column. This solution was treated with 1.7 liters of an anion exchanger in the
OH"-Form. Nach Filtrieren und Waschen des Harzes mit Wasser erhielt man eine Lösung, die 2,2% p-Toiuolsulfonsäure und 0,85% SAM enthielt. Man konzentriert die Lösung bei Umgebungstemperatur unter Vakuum auf 600 ml und gibt dann Aceton zu. Es wird ein weißes, pulvriges, mikrokristallines Salz ausgefällt, das geruchlos, hygroskopisch und sehr wasserlöslich (mehr als 25%) ist, wobei sich eine farblose Lösung bildet. Das Salz ist in Methanol oder Äthanol nicht sehr löslich und ist in Aceton, Methyläthylketon. Chloroform, höheren Alkoholen und Benzol unlöslich.OH "form. After filtering and washing the resin with water, a solution was obtained which contained 2.2% p-toluene sulfonic acid and 0.85% SAM. Man concentrate the solution to 600 ml at ambient temperature under vacuum and then add acetone. It a white, powdery, microcrystalline salt is precipitated that is odorless, hygroscopic and very is water-soluble (more than 25%), forming a colorless solution. The salt is in methanol or Ethanol is not very soluble and is in acetone, methyl ethyl ketone. Chloroform, higher alcohols and benzene insoluble.
Die Analysenergebnisse sind wie folgt:The analysis results are as follows:
Analyse: C36H46N6OmS4 (Molekulargewicht 915,1)
Berechnet: C 473, H 5,15, N 9,18, S 14,OO<>/o;
gefunden: C 46,9, H 53, N 9,2, S 13,8 %.Analysis: C 36 H 46 N 6 OmS 4 (molecular weight 915.1)
Calculated: C 473, H 5.15, N 9.18, S 14, 00 <> / o;
found: C 46.9, H 53, N 9.2, S 13.8%.
NH2 NH 2
Gefunden: p-Toluolsulfonsäure 55,8%,Found: p-toluenesulfonic acid 55.8%,
SAM 42.5%:SAM 42.5%:
berechnet: p-Toluolsulfoniäure 56,4%,calculated: p-toluenesulfonic acid 56.4%,
SAM 43,6%.SAM 43.6%.
Gewichtsverlust durch Trocknen während Ί2 Stunden bei Umgebungstemperatur im Vakuum über P2O5:1,5 bis 2%.Loss of weight on drying for Ί2 hours at ambient temperature in vacuo over P 2 O 5 : 1.5 to 2%.
Feuchtigkeit, bestimmi nach Karl Fischer: 1 5 bis 2%.Moisture, determined by Karl Fischer: 1 5 to 2%.
Das UV-Spektrum der neuen Verbindung zeigt einThe UV spectrum of the new compound shows a
Absorptionsmaximum bei 256 nm. E= 15 600 (in 6 η Schwefelsäure). Bei 260 nm, E= 16 300 (bei pH 7).Absorption maximum at 256 nm. E = 15,600 (in 6 η sulfuric acid). At 260 nm, E = 16,300 (at pH 7).
Alle diese Daten stehen in Einklang mit einerAll of these data are consistent with one
Verbindung der FormelCompound of formula
N N CH3 NH2 NN CH 3 NH 2
CH-CH-CH-CH-CH2-S-CH2-Ch2-CH-COOH · 2CH3-QH4-SOjH OH OHCH-CH-CH-CH-CH 2 -S-CH 2 -Ch 2 -CH-COOH · 2CH 3 -QH 4 -SOjH OH OH
-O--O-
CH3 Q1H4SO3 CH 3 Q 1 H 4 SO 3
Die neue Verbindung wurde ferner identifiziert durch die enzymatische Methode, die auf der enzymatischen Methylierung von Nicotinamid oder Guanidinessigsäure mit SAM beruht (G. L. C a η t ο η i, J. Biol. Chem. 189, 745[19")\\ ibid. 204,403[1953],G. De La Hoba, G. A. Jamieson, S. H. Mudd, H.H.Richards, ]. A. C. S. 81,3975 [1959]).The new compound was also identified by the enzymatic method based on the enzymatic methylation of nicotinamide or guanidine acetic acid with SAM (GL C a η t ο η i, J. Biol. Chem. 189, 745 [19 ") \\ ibid. 204, 403 [1953], G. De La Hoba, GA Jamieson, SH Mudd, HHRichards,]. ACS 81, 3975 [1959]).
9 kg Hefe werden wie in Beispiel 1 beschrieben behandelt. Nach Lysis der Zellen erhielt man 13,8 Liter einer Lösung, die 3,60 g/Liter SAM enthielt, was 99% des in dem behandelten Material anwesenden entspricht. Diese Lösung wird auf 1 Liter eines schwachsauren Kationenaustauschers in der H+-Form adsorbiert und mit Wasser, 0,025 η Essigsäure und einer 4 η HCl-Lösung eluiert. Die wie in Beispiel 1 bestimmten, an reinem SAM reichen Fraktionen entsprachen 0,8 Liter und enthielten 87% des in die Kolonne eingespeisten Produkts. Bei 40°C wird unter Vakuum zur Trockne eingedampft.9 kg of yeast are treated as described in Example 1. After lysing the cells, 13.8 liters were obtained a solution containing 3.60 g / liter of SAM, which is 99% of that present in the treated material. This solution is adsorbed on 1 liter of a weakly acidic cation exchanger in the H + form and eluted with water, 0.025 η acetic acid and a 4 η HCl solution. The determined as in Example 1, fractions rich in pure SAM corresponded to 0.8 liters and contained 87% of that in the column fed product. At 40 ° C., it is evaporated to dryness in vacuo.
Man gibt Wasser zu, bis eine 5%ige SAM-Lösung erhalten wird, wobei man die Lösung bei 0°C hält, und man gibt einen Anionenaustauscher in der OH~-Form zu, bis eine Probe der Lösung ergibt, daß keine Chloride vorhanden sind.Water is added until a 5% SAM solution is obtained, the solution being kept at 0 ° C., and an anion exchanger in the OH ~ form is added until a sample of the solution shows that there are no chlorides available.
Das Harz wird abfiltriert, 110 g p-Toluolsulfonsäure werden zugegeben ui.J man konzentriert auf 600 ml. Man gibt Methylalkohol zu, bis die Ausfällung vollständig ist. Nach Abfiltrieren und Trocknen erhält man SAM-Tri-p-toluolsulfonat, das die gleichen Eigenschaften wie das gemäß Beispiel 1 erhaltene aufweist.The resin is filtered off, 110 g of p-toluenesulfonic acid are added and concentrated to 600 ml. Methyl alcohol is added until the precipitation occurs is complete. After filtering off and drying, SAM-Tri-p-toluenesulfonate is obtained, which has the same properties as obtained according to Example 1.
13,8 Liter SAM-Lösung, die man nach Lysis der Hefezellen wie in Beispiel 2 beschrieben erhält (3,60 g/Liter SAM), adsorbiert man auf 1 Liter eines schwach-sauren Kationenaustauschers in der H+-Form und eluiert nacheinander mit Wasser, 0,025 molarer Essigsäure und schließlich mit 1 η Schwefelsäure.13.8 liters of SAM solution obtained after lysing the yeast cells as described in Example 2 (3.60 g / liter SAM), is adsorbed on 1 liter of a weakly acidic cation exchanger in the H + form and eluted successively with water, 0.025 molar acetic acid and finally with 1 η sulfuric acid.
Die am meisten SAM enthaltenden Fraktionen (1,8 Liter, 86% des in die Kolonne eingespeisten Produkts) behandelt man mit einer Suspension von Ba(OH)2 bei 0° C, bis Sulfate völlig eliminiert sind.The fractions containing the greatest amount of SAM (1.8 liters, 86% of the product fed into the column) are treated with a suspension of Ba (OH) 2 at 0 ° C. until sulfates are completely eliminated.
Nach Abfiltrieren und Waschen des Bariumsulfats gibt man 108 g p-Toluolsulfonsäure zu und arbeitet wie in Beispiel 2 beschrieben, wobei man ein Tri-p-toluolsulfonat von SAM erhält, das die gleichen Eigenschaften besitzt wie das gemäß Beispiel 1 erhaltene Produkt.After the barium sulfate has been filtered off and washed, 108 g of p-toluenesulfonic acid are added and the procedure is followed described in Example 2, using a tri-p-toluenesulfonate obtained from SAM, which has the same properties as the product obtained according to Example 1.
13,8 Liter Lösung, die 43,3 g SAM enthält, adsorbiert so man auf einer Harzkolonne und eluiert wie in Beispiel 2 mit wäßrigem HCl. Die an SAM reichen Fraktionen werden bei 40° im Vakuum zur Trockne eingedampft13.8 liters of solution containing 43.3 g of SAM are adsorbed on a resin column and eluted as in Example 2 with aqueous HCl. The fractions rich in SAM are evaporated to dryness at 40 ° in vacuo
Man gibt Wasser zu, bis man eine 10%ige SAM-Chloridlösung erhält, die durch Zugeben von Aceton ausgefällt wird. Das so erhaltene Salz hat dieWater is added until a 10% SAM chloride solution is obtained, which can be obtained by adding Acetone is precipitated. The salt thus obtained has the
folgenden Analyseneigenschaften:the following analysis properties:
Chloride 16,86%Chloride 16.86%
SAM 78,85%SAM 78.85%
H2O 4,2 % .H 2 O 4.2%.
10 g dieses Salzes löst man in 200 ml Wasser und eliminiert die Chloride bei 0° mit einem Kationenaustauscher in der OH"-Form. Zu der Lösung gibt man 19,7 g p-Toluolsulfonsäure, konzentriert die Mischung bei 40° im Vakuum auf 80 ml und gibt Aceton zu, um das Tri-p-toluolsulfonat von SAM auszufällen, das die gleichen Eigenschaften wie das gemäß Beispiel 1 hergestellte hat.10 g of this salt are dissolved in 200 ml of water and the chlorides are eliminated at 0 ° with a cation exchanger in the OH "form. 19.7 g of p-toluenesulfonic acid are added to the solution, and the mixture is concentrated at 40 ° in vacuo to 80 ml and acetone is added to precipitate the tri-p-toluenesulfonate from SAM, which the the same properties as that prepared according to Example 1 has.
13,8 Liter Lösung, die 3,60 g/Liter SAM enthalten und wie in Beispiel 3 beschrieben erhalten worden sind, adsorbiert man auf einer Kolonne eines schwach-sauren Kationenaustauscher, H+ -Form. Die an SAM reichen Fraktionen werden mit BaCC>3 behandelt, bis die molare Konzentration der Sulfate gleich der von SAM ist. Man filtriert die Lösung und konzentriert das Filtrat auf 500 ml. Mit Aceton wird ein Salz ausgefällt, das die folgenden Analyseneigenschaften hat:13.8 liters of solution containing 3.60 g / liter of SAM and have been obtained as described in Example 3, is adsorbed on a column of a weakly acidic Cation exchanger, H + form. The fractions rich in SAM are treated with BaCC> 3 until the molar Concentration of sulfates is the same as that of SAM. The solution is filtered and the filtrate is concentrated 500 ml. A salt is precipitated with acetone which has the following analytical properties:
SulfateSulfates
SAMSAM
H2OH 2 O
28,2%28.2%
58,9%58.9%
5,0%5.0%
10 g des so erhaltenen Salzes löst man in 120 ml Wasser und behandelt mit einem Anionenaustauscher,10 g of the salt thus obtained are dissolved in 120 ml of water and treated with an anion exchanger,
OH "-Form, bis das Sullation eliminiert ist. Nach Abfiltrieren des Harzes gibt man 14,7 g p-Toluolsulfonsäure zu, konzentriert die Mischung auf 60 ml und verwendet Aceton zur Ausfällung eines p-Toluolsulfonats von SAM, das die gleichen Eigenschaften wie das gemäß Beispiel 1 erhaltene hat.OH "form until the sullation has been eliminated. After the resin has been filtered off, 14.7 g of p-toluenesulphonic acid are added too, concentrate the mixture to 60 ml and use acetone to precipitate a p-toluenesulfonate from SAM, which has the same properties as that obtained in Example 1.
Beispie! 6Example! 6th
Ig SAM-Jodid (600mg SAM) löst man in 10ml Wasser und behandelt mit einem Kationenaustauscher in der OH"-Form bei 0°, bis das Jodidion eliminiert ist. Nach Abfiltrieren des Harzes gibt man 1,5 g p-Toluolsulfonsäure zu. konzentriert die Mischung auf 6 ml und verwendet Aceton, um das Tri-p-toluolsulfonat von SAM auszufällen, dessen Analyseneigenschaften mit denen des gemäß Beispiel 1 erhaltenen identisch sind.Ig SAM iodide (600mg SAM) is dissolved in 10ml Water and treated with a cation exchanger in the OH "form at 0 ° until the iodide ion is eliminated. After filtering off the resin, 1.5 g of p-toluenesulfonic acid are added to. concentrated the mixture to 6 ml and used acetone to make the tri-p-toluenesulfonate of To precipitate SAM, the analytical properties of which are identical to those obtained in Example 1.
Claims (1)
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| IE39517B1 (en) * | 1973-06-27 | 1978-10-25 | Bioresearch Sas | Double salts of s-adenosyl-l-methhionine |
| AR221676A1 (en) * | 1974-07-12 | 1981-03-13 | Bioresearch Sas | PROCEDURE FOR THE PREPARATION OF SULPHONIC AND / OR SULFURIC STABLE SALTS OF S-ADENOSIL-L-METIONINE, PARTICULARLY USEFUL AS SPECIFIC METHYL DONORS FOR THE CH3, ELAMIBLI-TRANSFERRING BIOCHEMICAL AND LATIN-GLOBAL ELEMENTS PROTILICO AND GLUCIDICO |
| US4109079A (en) * | 1975-10-16 | 1978-08-22 | Yamasa Shoyu Kabushiki Kaisha | Stabilized s-adenosyl-l-methionine preparations |
| GB2064523B (en) * | 1979-12-04 | 1983-06-29 | Kanegafuchi Chemical Ind | Stable composition of s-adenosyl-l-methionine |
| IT1137892B (en) * | 1981-08-24 | 1986-09-10 | Bioresearch Srl | STABLE SALTS OF S-ADENOSYLMETHIONINE, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE THEM AS AN ACTIVE PRINCIPLE |
| IT1137640B (en) | 1981-08-24 | 1986-09-10 | Bioresearch Srl | STABLE SALTS OF S-ADENOSYLMETHIONINE, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT INCLUDE THEM AS AN ACTIVE PRINCIPLE |
| IT1139974B (en) * | 1981-09-11 | 1986-09-24 | Bioresearch Srl | DERIVATIVES OF S-ADENOSYLMETHIONINE, PROCESS FOR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE INGREDIENT |
| IT1169774B (en) * | 1983-08-24 | 1987-06-03 | Bioresearch Spa | INJECTABLE THERAPEUTIC COMPOSITIONS CONTAINING STABLE SALTS OF S-ADENOSYL-METHIONINE |
| IT1169773B (en) * | 1983-08-24 | 1987-06-03 | Bioresearch Spa | PROCESS FOR THE PRODUCTION OF STABLE SALTS OF SULPHO-ADENOSYL-L-METHIONINE |
| IT1173990B (en) * | 1984-05-16 | 1987-06-24 | Bioresearch Spa | STABLE SALTS OF SULPHO-ADENOSYL-METHIONINE (SAME) PARTICULARLY SUITABLE FOR PARENTERAL USE |
| IT1173992B (en) * | 1984-05-16 | 1987-06-24 | Bioresearch Spa | STABLE SALTS OF SULPHO-ADENOSYL-METHIONINE (SAME) PARTICULARLY SUITABLE FOR ORAL PHARMACEUTICAL USE |
| IT1200589B (en) * | 1985-02-14 | 1989-01-27 | Gibipharma Spa | NATURAL DERIVATIVES PHARMAGOLOGICAL ACTIVITY |
| EP0395656B1 (en) * | 1987-10-09 | 1992-09-02 | ZAPPIA, Vincenzo | Lipophilic salts of s-adenosyl-l-methionine (sam) with acylated taurine derivatives |
| DE19515275A1 (en) * | 1995-04-26 | 1996-10-31 | Knoll Ag | New use of (S) -denosyl-L-methionine (SAMe) |
| US6759395B2 (en) | 2000-12-18 | 2004-07-06 | Orchid Chemicals & Pharmaceuticals, Ltd. | Soft-gelatin capsule comprising S-adenosylmethionine and a method for producing the same |
| US8063024B2 (en) * | 2005-01-26 | 2011-11-22 | University Of Manitoba | Use of S-adenosylmethionine, vitamin E, and vitamin C for the treatment of oxidative liver injury and insulin resistance |
| US20090012036A1 (en) * | 2005-05-24 | 2009-01-08 | Hebert Rolland F | Stable S-adenosyl-L-methionine |
| ITMI20060629A1 (en) | 2006-03-31 | 2007-10-01 | Daniele Giovannone | ORAL SOLID COMPOSITIONS BASED ON S-ADENOSYLMETIONINE AND PROCESS FOR THEIR ACHIEVEMENT |
| US20090197824A1 (en) * | 2008-01-31 | 2009-08-06 | Methylation Sciences International Srl | Extended Release Pharmaceutical Formulations of S-Adenosylmethionine |
| AU2008210327B2 (en) * | 2007-01-31 | 2011-06-16 | Methylation Sciences International Srl | Extended release pharmaceutical formulations of S-adenosylmethionine |
| US20090088404A1 (en) * | 2007-01-31 | 2009-04-02 | Methylation Sciences International Srl | Extended Release Pharmaceutical Formulations of S-Adenosylmethionine |
| ITMI20071374A1 (en) * | 2007-07-10 | 2009-01-11 | Gnosis Spa | STABLE STABLE OF S-ADENOSYLMETHIONINE AND PROCESS FOR THEIR ACHIEVEMENT. |
| US20100004191A1 (en) * | 2008-07-01 | 2010-01-07 | Rolland F Hebert | Compositions of S-adenosyl-L-methionine. |
| US20110027342A1 (en) * | 2009-07-28 | 2011-02-03 | Msi Methylation Sciences, Inc. | S-adenosylmethionine formulations with enhanced bioavailability |
| US8329208B2 (en) | 2009-07-28 | 2012-12-11 | Methylation Sciences International Srl | Pharmacokinetics of S-adenosylmethionine formulations |
| CN103906521A (en) | 2011-04-15 | 2014-07-02 | 塞玛尔有限公司 | Use of s-adenosylmethionine, vitamin e, and vitamin c for the prevention and treatment of cardiovascular dysfunction |
| ES2540581T3 (en) | 2012-10-17 | 2015-07-10 | Methylation Sciences International Srl | Compositions comprising S-adenosylmethionine and a gallic acid ester |
| WO2014113609A1 (en) | 2013-01-16 | 2014-07-24 | Hebert Sam-E Llc | Stable indole-3-propionate salts of s-adenosyl-l-methionine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2946781A (en) * | 1957-02-06 | 1960-07-26 | Merck & Co Inc | Process for the preparation of adenosyl homocysteine |
| US3642772A (en) * | 1968-09-04 | 1972-02-15 | Boehringer Mannheim Gmbh | Process for preparing s-adenosyl homocysteine |
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1973
- 1973-07-16 IE IE1192/73A patent/IE37913B1/en unknown
- 1973-07-17 DE DE2336401A patent/DE2336401C3/en not_active Expired
- 1973-07-17 US US380097A patent/US3893999A/en not_active Expired - Lifetime
- 1973-07-17 IL IL42764A patent/IL42764A/en unknown
- 1973-07-17 ZA ZA734876A patent/ZA734876B/en unknown
- 1973-07-19 FR FR7326500A patent/FR2194425B1/fr not_active Expired
- 1973-07-19 GB GB3449973A patent/GB1425384A/en not_active Expired
- 1973-07-25 RO RO7300075582A patent/RO63451A/en unknown
- 1973-07-26 YU YU2030/73A patent/YU36037B/en unknown
- 1973-07-26 CS CS735374A patent/CS195254B2/en unknown
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- 1973-08-01 DK DK422773A patent/DK131868C/en not_active IP Right Cessation
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- 1973-08-02 NL NL737310706A patent/NL152864B/en not_active IP Right Cessation
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- 1973-08-02 JP JP48086440A patent/JPS5235726B2/ja not_active Expired
- 1973-08-02 FI FI732438A patent/FI52466C/en active
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1980
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